There is a continuing need for analgesic medications which are suitable for effectively treating visceral pain and especially acute visceral pain. Deep pain from the internal organs is a common cause of visits to doctors and long-term sick leave in the western world. The causes for visceral pain can be sought in both organic and functional conditions, but what is common to these is that there is complex activation of the nervous system. In many cases, the visceral pain persists despite the original cause having been wholly or partially eliminated. In many cases morphine is currently used for the treatment of moderate to severe visceral pain.
There is also a continuing need for analgesic medications able to provide high efficacy pain relief while reducing the possibility of undesirable effects. Accordingly, it is most desirable to have analgesic medications which provide high efficacy pain relief at low dosages in order to avoid or at least reduce undesirable effects and especially side-effects observed at higher dosages or for certain specific analgesics.
Although opioids are prescribed with increasing frequency, knowledge of their effect on visceral pain is limited. However, it is known that, in addition to analgesic effects, morphine may also cause a number of undesirable effects, including, for example, respiratory depression, nausea, vomiting, dizziness, mental clouding, dysphoria, pruritus, constipation, increased biliary tract pressure, urinary retention and hypotension.
The effect of certain active agents on patients is highly variable. Visceral pain differs from pain in the skin in many ways and is often more difficult to treat.
In the literature different types of pain associated with disease of the viscera are suggested. These types comprise true or localized visceral pain, referred visceral pain, localized parietal pain, and referred parietal pain. The present invention especially refers to the treatment of true or localized visceral pain.
True visceral pain often occurs early in the disease and is characterized by a vague, diffuse, dull, aching pain, which is localized but can have a tendency to radiate. It can be accompanied by a feeling of malaise, and, when severe, it induces strong autonomic phenomena such as sweating, vasomotor responses, bradycardia, nausea and vomiting, and sometimes an alarm reaction. It is usually felt in the midline and deep in the body.
There are a variety of conditions in which visceral pain may exist. For example, pancreatitis pain, labor pain, pain from abdominal surgery associated with ileus, pain in irritable bowel syndrome, abdominal pain in nonulcer dyspepsia, or in dysmenorrhea. Likewise, liver pain, kidney pain, epigastric pain, pleural pain, and painful biliary colic, appendicitis pain may all be considered to be visceral pain. Substernal pain or pressure from early myocardial infarction is also visceral. Diseases of the stomach, dudenum or colon can cause visceral pain. And there are more.
According to an embodiment of the present invention it has been found that it is possible to effectively treat moderate to severe visceral pain by administering analgesic medications comprising the opioid oxycodone or pharmaceutically acceptable salts thereof. Moreover, it has been found that visceral pain and especially acute (i.e. non-chronic) visceral pain can be effectively treated by administering oxycodone at a dosage which is lower than the corresponding dosage of other opioids like morphine. Accordingly, the present invention inter alia refers to a method of effectively treating moderate to severe visceral pain by administering oxycodone at relatively low dosages.
According to an embodiment of the present invention it has been found that treating visceral pain with a specific dosage of oxycodone is more effective than treating the same visceral pain with a higher corresponding dosage of morphine, whereas almost the same effect is observed if cutaneous or muscular pain is treated by administering corresponding dosages of oxycodone or morphine. In other words, according to the present invention it has been found that visceral pain and especially acute moderate to severe visceral pain can be effectively treated by administering oxycodone at relatively low dosages, whereas the “corresponding dosage” of morphine would be less effective in treating the same visceral pain. According to the present invention the “corresponding dosage” of morphine does not mean the same quantitative amount of morphine, but refers to the usual equipotent amount of morphine, i.e. to the amount of morphine which usually provides a similar pain relief to the patient. The usual equipotent weight ratio of morphine to oxycodone for oral administration is about 2:1 (the corresponding molar ratio is about 1.8:1).
According to another embodiment of the invention a method of selectively treating moderate to severe visceral pain in a patient is provided, the method comprising administering oxycodone in an effective amount to provide analgesia in the patient in need thereof. The present invention for the first time allows for the selective treatment of moderate to severe visceral pain, since it was not known prior to the present invention that this specific pain can be effectively treated by administering oxycodone at low dosages, whereas other opioids (like morphine) at dosages, which would have been considered equipotent by the skilled person, are less effective. Patients suffering exclusively from acute visceral pain, according to the present invention would not or no longer be treated with the opioids commonly used for this purpose (like morphine, hydromorphone, oxymorphone, codeine, and hydrocodone) but with oxycodone. Accordingly, the present invention opens a new therapeutic window for the opioid oxycodone.
According to another embodiment of the invention a method of treating moderate to severe visceral pain in a patient already being treated with morphine or a salt thereof is provided, the method comprising:
(a) discontinuing treatment with morphine; and
(b) administering oxycodone or a salt thereof in an amount of less than 50% by weight of the morphine or salt thereof.
According to another embodiment of the invention a method of treating moderate to severe visceral pain in a patient already being treated with hydromorphone, oxymorphone, codeine, hydrocodone or salts thereof is provided, the method comprising:
(a) discontinuing treatment with hydromorphone, oxymorphone, codeine, hydrocodone or salts thereof; and
(b) administering oxycodone or a salt thereof in an amount of less than the equipotent weight of the hydromorphone, oxymorphone, codeine, hydrocodone or salts thereof.
An embodiment of the present invention also allows the treatment of acute visceral pain by administering oxycodone at a dosage which is sufficiently low in order to reduce or avoid undesired side effects. This means, that therapeutic levels can be achieved without or with fewer concurrent side effects, such as nausea, vomiting, constipation and drowsiness, which may be associated with high blood levels of oxycodone.
The finding that visceral pain can be effectively treated by administering low dosages of oxycodone allows for the use of immediate release formulations and sustained release formulations. It may be preferred according to the present invention to treat visceral pain and especially acute visceral pain by administering oxycodone-containing once-a-day, twice-a-day, three-times-a-day, or four-times-a-day dosage forms. According to the present invention it may be especially preferred to use oxycodone-containing sustained release formulations, wherein the dosage does not exceed 40 mg oxycodone, preferably does not exceed 30 mg oxycodone and even more preferably does not exceed 10 mg oxycodone. According to the present invention it may be most preferred to use oxycodone-containing sustained release formulations and preferably once-a-day, twice-a-day, three-times-a-day, or four-times-a-day dosage forms comprising about 10 mg, about 9 mg, about 8 mg, about 7 mg, about 6 mg or about 5 mg oxycodone. It is also preferred in certain embodiments to use single-entity oxycodone or salts thereof, e.g., oxycodone or salts thereof without APAPs or other active agents.